The absent, small, or homeotic-like 1 (ASH1L) protein is a histone lysine methyltransferase that plays a crucial role in various cancers, including leukemia. Despite representing an attractive therapeutic target, only one class of ASH1L inhibitors was identified to date. Herein, we report development of advanced ASH1L inhibitors targeting the catalytic SET domain, which were designed to access previously unexplored binding pocket on ASH1L. Extensive medicinal chemistry combined with structure-based design led to identification of 66s (AS-254s), a highly potent and selective ASH1L inhibitor (IC₅₀ = 94 nM), representing substantially improved inhibitory activity over previously reported compounds targeting ASH1L. Furthermore, 66s effectively blocked cell proliferation and induced apoptosis and differentiation in leukemia cells harboring MLL1 translocations. Overall, this work provides a high-quality chemical probe targeting the catalytic SET domain of ASH1L with increased inhibitory activity and cellular efficacy to study biological functions of ASH1L and potentially to develop novel anticancer therapeutics.

中文翻译：

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新型螺哌啶 ASH1L 抑制剂的基于结构的开发


缺失、小或同源样 1 （ASH1L） 蛋白是一种组蛋白赖氨酸甲基转移酶，在包括白血病在内的各种癌症中起着至关重要的作用。尽管代表了一个有吸引力的治疗靶点，但迄今为止仅确定了一类 ASH1L 抑制剂。在此，我们报道了靶向催化 SET 结构域的先进 ASH1L 抑制剂的开发，这些抑制剂旨在进入以前未探索的 ASH1L 结合口袋。广泛的药物化学结合基于结构的设计导致鉴定出 66s （AS-254s），一种高效且选择性的 ASH1L 抑制剂 （IC₅₀ = 94 nM），与先前报道的靶向 ASH1L 的化合物相比，抑制活性显着提高。此外，66s 有效阻断了细胞增殖，并诱导了携带 MLL1 易位的白血病细胞凋亡和分化。总体而言，这项工作提供了一种靶向 ASH1L 催化 SET 结构域的高质量化学探针，具有更高的抑制活性和细胞功效，用于研究 ASH1L 的生物学功能，并有可能开发新的抗癌疗法。